Epidermal growth factor receptor (EGFR) targeted therapy
is one
of the most important and effective strategies to combat EGFR mutant
nonsmall-cell lung cancer (NSCLC). However, a substantial number of
patients bearing EGFR exon 20 insertion (Ex20ins) mutations respond
poorly to common EGFR targeted therapies. This clinical need remained
unmet until recently, when the EGFR Ex20ins mutation inhibitor mobocertinib
was approved by the FDA. Despite this progress, the structural mechanisms
of EGFR Ex20ins mutation resistance and characterization of inhibitor
binding modes have not been systematically summarized. Herein, we
analyze the structural mechanisms for ligand binding and resistance
and summarize recent developments for the reported inhibitors of EGFR
Ex20ins mutations. Furthermore, this Perspective aims to provide insights
for the design of the next generation of EGFR Ex20ins inhibitors.